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Abstract

Pre-term birth (PTB) is a major health challenge to-day. Perinatal mortality is increased more than three times and PTB is the leading cause of short and long-term neonatal/infant morbidity. Many are the risk factors, previous PTB, cervical effacement or dilatation on clinical vaginal examination or shortening of the length of the cervical canal on ultrasound are major predisposing factors.

A growing body of evidence suggests that progesterone plays a role in preventing PTB. Progesterone decreases prostaglandin synthesis, reduces cervical stromal degradation, alters the barrier to inflammation and ascending infection in the cervix, reduces gap junction formation, decreases the conduction and frequency of myometrial contractions, increases the stimulation threshold of the myometrium and decreases spontaneous myometrial activity.

Progesterone, and other progestogens, have been tested in clinical trials for the prevention of PTB. The three main groups of patients evaluated included: patients with a previous preterm birth, patients with a short cervix at mid gestation and patients with twin pregnancy. Micronized progesterone given by the vaginal route has been found to reduce the incidence of PTB in the first two indications by approximately 50 %, while 17 OH progesterone caproate is effective only on patients with previous PTB. In twin pregnancy neither compound seems to significantly prolong pregnancy although a beneficial effect has been demonstrated on neonatal composite morbidity using vaginal micronized progesterone. Universal cervical length screening and vaginal progesterone treatment (90 mg vaginal gel or 200 mg micronized soft gel suppositories) is also a cost-effective model for the prevention of PTB.

The administration of high-dosage micronized progesterone has been advocated as a possible tocolytic agent. However, the slow action requires additional tocolytic agents such as β-agonists, prostaglandin synthesis inhibitors or calcium channel blockers in the case of acute tocolysis. Finally micronised progesterone can be used for the maintenance of uterine quiescence in patients previously treated for an episode of threatened preterm labour.

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References

  1. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371:75–84.

    Article  PubMed  Google Scholar 

  2. Haas DM. Preterm birth. Clin Evid. 2011, pii: 1404.

    Google Scholar 

  3. Di Renzo GC, Cutuli A, Liotta L, Burnelli L, Luzi G. Management of preterm labor: pharmacological and nonpharmacological aspects. In: Textbook of perinatal medicine. 2nd eds, Kurjak A, Chervenak FA. Informa Healthcare; 2006. Cap. 130, pp. 1394–1400.

    Google Scholar 

  4. Druckmann R, Druckmann MA. Progesterone and the immunology of pregnancy. J Steroid Biochem Mol Biol. 2005;97:389–96.

    Article  CAS  PubMed  Google Scholar 

  5. Szekeres-Bartho J, Barakonyi A, Par G, Polgar B, Palkovics T, Szereday L. Progesterone as an immunomodulatory molecule. Int Immunopharmacol. 2001;1:1037–48.

    Article  CAS  PubMed  Google Scholar 

  6. Di Renzo GC, Giardina I, Clerici G, Mattei A, Alajmi AH, Gerli S. The role of progesterone in maternal and fetal medicine. Gynecol Endocrinol. 2012;28:925–32.

    Article  PubMed  Google Scholar 

  7. Schwartz N, Xue X, Elovitz MA, Dowling O, Metz CN. Progesterone suppresses the fetal inflammatory response ex vivo. Am J Obstet Gynecol. 2009;201:211.

    PubMed  Google Scholar 

  8. Fanchin R, Ayoubi JM, Olivennes F, Righini C, de Ziegler D, Frydman R. Hormonal influence on the uterine contractility during ovarian stimulation. Hum Reprod. 2000;15 Suppl 1:90–100.

    Article  CAS  PubMed  Google Scholar 

  9. Perusquía M, Jasso-Kamel J. Influence of 5alpha- and 5beta-reduced progestins on the contractility of isolated human myometrium at term. Life Sci. 2001;68:2933–44.

    Article  PubMed  Google Scholar 

  10. Chanrachakul B, Broughton Pipkin F, Warren AY, Arulkumaran S, Khan RN. Progesterone enhances the tocolytic effect of ritodrine in isolated pregnant human myometrium. Am J Obstet Gynecol. 2005;192:458–63.

    Article  CAS  PubMed  Google Scholar 

  11. Liu J, Matsuo H, Laoag-Fernandez JB, Xu Q, Maruo T. The effects of progesterone on apoptosis in the human trophoblast-derived HTR-8/SV neo cells. Mol Hum Reprod. 2007;13:869–74.

    Article  CAS  PubMed  Google Scholar 

  12. Czajkowski K, Sienko J, Mogilinski M, Bros M, Szczecina R, Czajkowska A. Uteroplacental circulation in early pregnancy complicated by threatened abortion supplemented with vaginal micronized progesterone or oral dydrogesterone. Fertil Steril. 2007;87:613–8.

    Article  CAS  PubMed  Google Scholar 

  13. Jacobsson B, Mattsby-Baltzer I, Andersch B, Bokström H, Holst RM, Wennerholm UB, Hagberg H. Microbial invasion and cytokine response in amniotic fluid in a Swedish population of women inpreterm labor. Acta Obstet Gynecol Scand. 2003;82:120–8.

    Article  PubMed  Google Scholar 

  14. Raghupathy R, Al Mutawa E, Makhseed M, Azizieh F, Szekeres-Bartho J. Modulation of cytokine production by dydrogesterone in lymphocytes from women with recurrent miscarriage. BJOG. 2005;112:1096–101.

    Article  CAS  PubMed  Google Scholar 

  15. Hudic I, Szekeres-Bartho J, Fatusic Z, et al. Dydrogesterone supplementation in women with threatened preterm delivery – the impact on cytokine profile, hormone profile, and progesterone-induced blocking factor. J Reprod Immunol. 2011;92:103–7.

    Article  CAS  PubMed  Google Scholar 

  16. Aisemberg J, Vercelli CA, Bariani MV, Billi SC, Wolfson ML, Franchi AM. Progesterone is essential for protecting against LPS-induced pregnancy loss. LIF as a potential mediator of the anti-inflammatory effect of progesterone. PLoS One. 2013;8:e56161. Epub 2013 Feb 7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Di Renzo GC, Rosati A, Mattei A, Gojnic M, Gerli S. The changing role of progesterone in preterm labour. BJOG. 2005;112 Suppl 1:57–60.

    Article  PubMed  Google Scholar 

  18. Karteris E, Zervou S, Pang Y, Dong J, Hillhouse EW, Randeva HS, Thomas P. Progesterone signaling in human myometrium through two novel membrane G protein- coupled receptors: potential role in functional progesterone withdrawal at term. Mol Endocrinol. 2006;20:1519–34.

    Article  CAS  PubMed  Google Scholar 

  19. Merlino AA, Welsh TN, Tan H, Yi LJ, Cannon V, Mercer BM, Mesiano S. Nuclear progesterone receptors in the human pregnancy myometrium: evidence that parturition involves functional progesterone withdrawal mediated by increased expression of progesterone receptor-A. J Clin Endocrinol Metab. 2007;92:1927–33.

    Article  CAS  PubMed  Google Scholar 

  20. Ruddok NK, Shi SQ, Jain S, Moore G, Hankins GDV, Romero R, Garfield RE. Progesterone, but not 17-alpha-hydroxyprogesterone caproate, inhibits human myometrial contractions. Am J Obstet Gynecol. 2008;199(391):e1–7.

    Google Scholar 

  21. Keirse MJ. Progestogen administration in pregnancy may prevent preterm delivery. Br J Obstet Gynaecol. 1990;97:149–54.

    Article  CAS  PubMed  Google Scholar 

  22. Di Renzo GC, Mattei A, Gojnic M, Gerli S. Progesterone and pregnancy. Curr Opin Obstet Gynecol. 2005;17:598–600.

    Article  PubMed  Google Scholar 

  23. Nahoul K, Dehennin L, Scholler R. Radioimmunoassay of plasma progesterone after oral administration of micronized progesterone. J Steroid Biochem. 1987;26:241–9.

    Article  CAS  PubMed  Google Scholar 

  24. Zava DT, Dollbaum CM, Blen M. Estrogen and progestin bioactivity of foods, herbs, and spices. Proc Soc Exp Biol Med. 1998;217:369–78.

    Article  CAS  PubMed  Google Scholar 

  25. Fitzpatrick LA, Good A. Micronized progesterone: clinical indications and comparison with current treatments. Fertil Steril. 1999;72:389–97.

    Article  CAS  PubMed  Google Scholar 

  26. Bulletti C, de Ziegler D, Flamigni C, Giacomucci E, Polli V, Bolelli G, Franceschetti F. Targeted drug delivery in gynaecology: the first uterine pass effect. Hum Reprod. 1997;12:1073–9.

    Article  CAS  PubMed  Google Scholar 

  27. Cicinelli E, de Ziegler D, Bulletti C, Matteo MG, Schonauer LM, Galantino P. Direct transport of progesterone from vagina to uterus. Obstet Gynecol. 2000;95:403–6.

    Article  CAS  PubMed  Google Scholar 

  28. Kamat S, Veena P, Rani R. Comparison of nifedipine and progesterone for maintenance tocolysis after arrested preterm labour. J Obstet Gynaecol. 2014;34(4):322–5. Epub ahead of print.

    Article  CAS  PubMed  Google Scholar 

  29. Di Renzo GC, Cabero Roura L, Facchinetti F, The European Association of Perinatal Medicine-Study Group on “Preterm Birth”. Guidelines for the management of spontaneous preterm labour. Identification of spontaneous preterm labor, diagnosis of preterm premature rupture of membranes and preventive tools for preterm birth. J Matern Fetal Neonatal Med. 2011;24:659–67.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Goldstein P, Berrier J, Rosen S, Sacks HS, Chalmers TC. A meta-analysis of randomized control trials of progestational agents in pregnancy. Br J Obstet Gynaecol. 1989;96:265–74.

    Article  CAS  PubMed  Google Scholar 

  31. Daya S. Efficacy of progesterone support for pregnancy in women with recurrent miscarriage. A meta-analysis of controlled trials. Br J Obstet Gynaecol. 1989;96:275–80.

    Article  CAS  PubMed  Google Scholar 

  32. Erny R, Pigne A, Prouvost C, Gamerre M, Malet C, Serment H, Barrat J. The effects of oral administration of progesterone for premature labor. Am J Obstet Gynecol. 1986;154:525–9.

    Article  CAS  PubMed  Google Scholar 

  33. Barton JR, Barton LA, Istwan NB, Rhea DJ, Desch CN, Sibai BM. 17-Alphahydroxyprogesterone caproate in women with previous spontaneous preterm delivery: does a previous term delivery affect the rate of recurrence? Am J Obstet Gynecol. 2011;205:269.e1–6.

    Article  Google Scholar 

  34. da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol. 2003;188:419–24.

    Article  PubMed  Google Scholar 

  35. Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O’Brien JM, Cetingoz E, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol. 2012;206:124.e1–19.

    Article  CAS  Google Scholar 

  36. Grobman WA, Thom EA, Spong CY, Iams JD, Saade GR, Mercer BM, Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network, et al. 17 Alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm. Am J Obstet Gynecol. 2012;207:390.e1–8.

    Article  CAS  Google Scholar 

  37. Maher MA, Abdelaziz A, Ellaithy M, Bazeed MF. Prevention of preterm birth: a randomized trial of vaginal compared with intramuscularprogesterone. Acta Obstet Gynecol Scand. 2013;92:215–22.

    Article  PubMed  Google Scholar 

  38. Hartikainen-Sorri AL, Kauppila A. Tuimala R Inefficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of prematurity in twin pregnancy. Obstet Gynecol. 1980;56:692–5.

    CAS  PubMed  Google Scholar 

  39. Combs CA, Garite T, Maurel K, Das A, Porto M, Obstetrix Collaborative Research Network. 17-Hydroxyprogesterone caproate for twin pregnancy: a double-blind, randomized clinical trial. Am J Obstet Gynecol. 2011;204:221.e1–8.

    Article  Google Scholar 

  40. Kurjak A, Chervenak FA. Management of preterm labor: pharmacological and non-pharmacological aspects. In: Textbook of perinatal medicine. 2nd ed. Informa Healthcare; 2006. Cap. 130, pp. 1394–1400.

    Google Scholar 

  41. Baumbach J, Shi SQ, Shi L, Balducci J, Coonrod DV, Garfield RE. Inhibition of uterine contractility with various tocolytics with and without progesterone: in vitro studies. Am J Obstet Gynecol. 2012;206:254.e1–5.

    Google Scholar 

  42. Borna S, Sahabi N. Progesterone for maintenance tocolytic therapy after threatened preterm labour: a randomised controlled trial. Aust N Z J Obstet Gynaecol. 2008;48:58–63.

    Article  PubMed  Google Scholar 

  43. Society for Maternal-Fetal Medicine Publications Committee, with assistance of Vincenzo Berghella. Progesterone and preterm birth prevention: translating clinical trials data into clinical practice. Am J Obstet Gynecol. 2012;206:376–86.

    Article  Google Scholar 

  44. Farine D, Mundle WR, Dodd J, Basso M, Delisle MF, Farine D, Maternal Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada, et al. The use of progesterone for prevention of preterm birth. J Obstet Gynaecol Can. 2008;30:67–77.

    PubMed  Google Scholar 

  45. Miles RA, Paulson RJ, Lobo RA, Press MF, Dahmoush L, Sauer MV. Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study. Fertil Steril. 1994;62:485–90.

    CAS  PubMed  Google Scholar 

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Correspondence to Gian Carlo Di Renzo MD,PhD,FRCOG(hon),FACOG(hon) .

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Di Renzo, G.C., Giardina, I., Babucci, G., Antonelli, C., Gerli, S., Clerici, G. (2015). Progestogens in Preterm Labour. In: Carp, H. (eds) Progestogens in Obstetrics and Gynecology. Springer, Cham. https://doi.org/10.1007/978-3-319-14385-9_6

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